Saturday, March 5, 2016

Sensing of RNA:DNA heteroduplexes by cGAS/STING pathway mirrors human autoimmune Aicardi–Goutières syndrome

Autoimmune diseases occur when bodies immune system continues to respond to self-antigens. Ordinarily, such [mis]directed responses are ascribed to adaptive immune system which possesses myriads of randomly generated receptors. So it is quite reasonable to assume that some of those receptor equipped clones (T or B cells) could go haywire and attack their own body's particular antigen or set of antigens. There are few autoimmune diseases known thus far that fall in this category (e.g. in Graves' disease, thyroid stimulating immunoglobulin [over]stimulates the same receptor that normally responds to only thyroid stimulating hormone). This is what is called lack or break of tolerance [mostly due to cross-reactivity]. 

However, much larger category of autoimmune diseases are due to genetic defects of different kind. These conditions harbor mutations in "housekeeping" molecules that are required for proper cellular homeostasis. Such mutations leads to immunopathologies that target broad spectrum of antigens or could even be restricted solely to the activation of innate immune system.    

For example, mutations in enzymes that ordinarily degrades self-DNA could lead to systemic immunopathologies due to activation of DNA sensing molecules cGAS or STING.

One such genetic mutation in ribonuclease (RNase) H2B (a enzyme that degrades cellular RNA:DNA heteroduplexes) leading to pathological cGAS/STING activation was recently described in the EMBO Journal.

This study revealed that mutation in RNase H2B that renders it less active led to up-regulation of interferon‐stimulated gene (ISG) transcripts. 

Follow-up experiments confirmed that interferon "signature" in RNase H2B KO cells was driven by cGAS (deletion via CRISPR/Cas9 genome editing) and STING activation (STING KO).

Exactly what type of self-DNA is detected that leads to cGAS and STING activation in cells with RNase H2B mutation is not yet clear. It could be (a) cytosolic RNA:DNA heteroduplexes accumulated as a consequence of reduced RNA:DNA degradation, or it could be (b) cytoplasmic DNA with embedded ribonucleotides that may accumulate due to impaired ribonucleotide excision repair (RER).

With the advance of human genomic testing, it is becoming evident that large portion of autoimmune diseases / immunopathologies may have a clear genetic basis and could be specifically targeted for therapeutic purpose.

David Usharauli

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